Are symptomatic guidelines for chemotherapy appropriate to ER-positive screen-detected breast cancer...

PRECLINICAL STUDY

Are symptomatic guidelines for chemotherapy appropriateto ER-positive screen-detected breast cancer (SDBC)?

Nigel J. Bundred • Ramachandran Prasad •

Julie Morris • W. Fiona Knox • Ged Byrne •

Shan Cheung • Mary Wilson • Gill Lawrence

Received: 23 November 2010 / Accepted: 21 June 2011 / Published online: 10 July 2011

� Springer Science+Business Media, LLC. 2011

Abstract Oncologists recommend chemotherapy to post-

menopausal women with adverse prognostic factors, but

predictors of the benefit of chemotherapy are mainly based

on mortality from symptomatic cancer trials. From 1990 to

1998, 1475 breast cancers (875 screen detected cancers

[SDBCs]: 600 symptomatic) were treated in women aged

50–65 years and prognostic factors compared with cancer

mortality. Median follow-up was 110 months. The Not-

tingham Prognostic Index (NPI) was calculated for 6737

breast cancers which were part of the Association of Breast

Surgery (ABS) 2001/2002 Audit of SDBCs to validate sur-

vival figures. Ten year survival was 92.1% for SDBC and

77.6% for symptomatic cancers. Adjusting for baseline

factors, SDBCs had a reduced mortality (RR = 0.42

(0.31–0.57), independent of grade, node status and tumour

size. Oestrogen receptor (ER) positive SDBC had a lower

annual mortality rate (0.6%) compared with symptomatic

(4.3%: P \ 0.001) or ER negative SDBC (1.8%). Epithelial

proliferation was lower in SDBC in all NPI groups compared

with symptomatic cancers (P B 0.001). Grade, node status,

ER status, size and mode of detection predicted survival.

Survival for each NPI group was better for SDBC. For ER

positive SDBC in the Moderate Prognostic Group 1 (MPG1),

10 year mortality was 6.4% compared with 17.6% in

symptomatic (P = 0.001). NPI on 6,737 operable SDBC

confirmed similar mortality in all groups (4% mortality in

MPG1 group). SDBC have lower mortality than symptom-

atic due to a lower proliferative index. The use of adjuvant

chemotherapy is over-treatment for ER positive SDBCs with

Good Prognostic Group (GPG) and MPG1 NPI scores.

Keywords Breast cancer � Epithelial proliferation �Screening

Abbreviations

ABS Association of Breast Surgery

EBCTCG Early Breast Cancer Trialists’ Collaborative

Group

Electronic supplementary material The online version of thisarticle (doi:10.1007/s10549-011-1652-6) contains supplementarymaterial, which is available to authorized users.

N. J. Bundred (&) � R. Prasad � G. Byrne

Academic Department of Surgery, University Hospital of South

Manchester, 2nd Floor Education and Research Centre,

Southmoor Road, Wythenshawe,

Manchester M23 9LT, UK

e-mail: [email protected]

R. Prasad


G. Byrne


J. Morris

Academic Department of Statistics, University Hospital of South

Manchester, Manchester, UK


W. F. Knox

Academic Department of Pathology, University Hospital of

South Manchester, Manchester, UK


S. Cheung � G. Lawrence

West Midlands Cancer Intelligence Unit, Manchester, UK


G. Lawrence


M. Wilson

Academic Department of Radiology and Statistics, University

Hospital of South Manchester, Manchester, UK


123

Breast Cancer Res Treat (2013) 138:359–368

DOI 10.1007/s10549-011-1652-6

http://dx.doi.org/10.1007/s10549-011-1652-6

EPG Excellent Prognostic Group

ER Oestrogen receptor

GPG Good Prognostic Group

MPG1 Moderate Prognostic Group 1

MPG2 Moderate Prognostic Group 2

NHSBSP National Health Service Breast Screening

Programme

NICE National Institute for Health and Clinical

Excellence

NPI Nottingham Prognostic Index

PPG Poor Prognostic Group

PR Progesterone receptor

SDBC Screen detected breast cancer

UHSM University Hospital of South Manchester

WLE Wide local excision

Introduction

Breast screening reduces mortality from breast cancer [1–

3]. Cancers detected by screening should require less

treatment as they are at an earlier stage [1–7]. Survival

figures for the Swedish Two Counties Trial demonstrated

small, node-negative cancers detected by screening had on

average, 8–10% better survival at 15 years compared with

similar-sized node negative, symptomatic cancers; despite

no adjuvant therapy being given [3].

Finnish comparison of palpable and non-palpable T1

cancers indicated a better breast cancer-specific survival in

non-palpable tumours, suggesting an inherent biological

difference in cancers detected by mammographic screening

[6]. Treatment decisions for breast cancer are now based on

molecular phenotype, with Oestrogen receptor (ER) nega-

tive and HER2 positive cancers advised chemotherapy.

Dawson et al. found screen detected luminal A (ER posi-

tive, HER2 negative) breast cancers had a 94% 15 year

survival compared with 84% for symptomatically detected

cancers [7]. Moreover, a UK population-based study found

that cancers detected by screening had a 50% lower mor-

tality than symptomatic cancers [8]. In general, the poorer

breast cancer survival in the UK reflects later diagnosis;

especially in older women [9].

Therapy for SDBC is determined by oncologists using

cancer guidelines developed mainly from trials for symp-

tomatic breast cancer [10, 11]. The Meta-analyses of the

Early Breast Cancer Trialists’ Collaborative Group (EB-

CTCG) recommended adjuvant chemotherapy for women

between 50 and 70 years old with adverse prognostic fac-

tors based on a 10–20% relative reduction in cancer mor-

tality [10] The benefit of chemotherapy is proportionate to

the risk of recurrence but complications of chemotherapy,

which include thrombosis, sepsis and occasionally death,

occur in 1–3% of treated patients and complications

increase with age [10–12]. Late adverse health effects such

as leukaemia and cardiotoxicity occur in 1% of patients

from 5–13 years later [13] The reduction in absolute

mortality from chemotherapy in postmenopausal women

older than 50 years was 3–5% [10] remaining constant at

15 years [10] and occurred within 5 years of chemotherapy

administration. Unless an individual’s risk of death is

greater than 10% at 5 years, no proportionate reduction in

mortality from chemotherapy use greater than 1% is

achievable, and the morbidity from its administration will

equal its benefit. Only breast cancers with an increased

annual hazard rate for mortality of 10% or greater in the

5 years after diagnosis will benefit from chemotherapy.

International Guidelines utilise pathological factors to

recommend chemotherapy [10, 11, 14, 15]. The UK NICE

guidelines recommend the use of Adjuvant! Online [11] to

select for adjuvant therapy. Clinicians use symptomatic

prognostic indices such as the Nottingham Prognostic

Index (NPI) which predicts survival based on histological

grade, lymph node status and 20% of the tumour size;

stratifying women with symptomatic breast cancer into five

different prognostic groups [15, 16]. Chemotherapy is

offered to Moderate (MPG1 and 2) and Poor Prognostic

Groups (PPGs) with overall 10 year survival 85%, 70%

and 36%, respectively [15, 16]. When the NPI was applied

to the 1996/1997 NHS Breast Screening Programme

(NHSBSP) data, the 5 year survival for SDBCs in MPG1, 2

and PPG was 94.2%, 87.4% and 71.5%, respectively [17].

This led us to investigate whether SDBCs have a lower

mortality from cancer, despite the presence of histopa-

thological adverse prognostic factors.

Annual Hazard Rates for mortality in women in the

50–65 year old age group were calculated to determine

within breast cancers with similar prognostic factors,

whether mode of detection is of prognostic value. To

identify women with ER positive SDBC at high risk of

mortality who require adjuvant chemotherapy, we used the

NPI and validated the results on 6737 operable SDBCs

submitted to the NHSBSP/ABS Audit. The ER positive

SDBCs had a better survival than symptomatic cancers

with a low mortality in the first 5 years, despite the omis-

sion of chemotherapy. This survival benefit is due to a

lower epithelial proliferation in SDBC, providing a bio-

logical rationale, and a reason why chemotherapy would be

less effective [18].

Materials and methods

In total, 1475 women with operable breast cancers (875

SDBCs and 600 symptomatic) were diagnosed and treated

360 Breast Cancer Res Treat (2013) 138:359–368

123

in women aged 50–65 years in the Manchester Breast Unit

between 1990 and 1998. Prospective follow-up data were

collected on all women (4.7% [n = 75] were lost to follow-

up). All patients in the Manchester part of the study were

diagnosed and treated by five surgeons in the South Man-

chester breast unit. They consented to follow-up and col-

lection of their data but the study was not submitted for

ethical approval as the data was taken from the outcomes of

the patient National ABS at BASO Audit supported by the

NHSBSP which does not require ethical approval, as the

auditing is done on an annual basis and has been approved

by the Department of Health (Fig. 1).

Pathological data (type, size, grade and node status), ER

and progesterone receptor (PR) status were prospectively

recorded on all patients (using NHSBSP reporting stan-

dards) in the University Hospital of South Manchester

(UHSM) Breast database. Cancer size was measured his-

tologically and expressed in mm. Tumours were graded by

the modified Bloom and Richardson method [19]. Median

follow-up was 110 months (range 15–187).

Women with palpable invasive cancer underwent wide

local excision (WLE) or mastectomy whenever possible.

Impalpable lesions were excised using localisation tech-

niques. Between 1990 and 1998, Unit policy was to per-

form a level III axillary clearance during the primary

procedure, if a pre-operative diagnosis was available or as

a subsequent procedure if no pre-operative diagnosis was

obtained, as sentinel node biopsy was not available in the

U.K. In women who underwent WLE by wire localisation

when grade I and II tumours \10 mm diameter were

removed, no axillary surgery was undertaken [20].

Adjuvant chemotherapy was given to women who had

tumours measuring more than 20 mm, ER negative can-

cers, or with 4 or more involved nodes. Adjuvant

Tamoxifen was given to all women with ER positive

tumours greater than 10 mm until 1995, when it was

offered to all ER positive tumours. The follow-up proto-

col observed was uniform. Women were examined

annually to 10 years with annual mammograms. The ER/

PR status was assessed by immuno-histochemistry on

paraffin slides as previously described [21]. Sections with

more than 5% of cell nuclear staining were considered

ER/PR positive [21]. Epithelial proliferation was assessed

by Ki67 staining and counting the number of cells stained

per 1,000 as previously described [21]. Immunohisto-

chemical detection and scoring of HER2 was as previ-

ously described [21] with scores 3? rated as positive. The

characteristics of the two populations of cancers are

shown in Table 1.

A clinically, radiologically or morphologically-verified

recurrence (any recurrence in the supraclavicular nodes or

beyond) and all deaths from breast cancer, were defined

as distant recurrence in the analysis. After comparing

mortality for SDBC and symptomatic cancers, the NPI

index was employed to determine the risk of mortality

and annual Hazard Rates for death calculated for both

groups.

Table 1 Prognostic factors in SDBC and symptomatic cancers in

Manchester (n = 1475)

Variables Symptomatic

n (%)

N = 600

Screening

n (%)

N = 875

P value

Size

\15 mm 217 (36.2) 536 (61.3)

15–25 mm 287 (47.8) 275 (31.4) P \ 0.001

[25 mm 96 (16.0) 64 (7.3)

Grade

I 165 (27.5) 238 (27.2)

II 258 (43.0) 358 (40.9) P = 0.60

III 177 (29.5) 279 (31.9)

Node status

Negative 392 (65.3) 692 (79.1) P \ 0.001

Positive (1–3 nodes) 149 (24.8) 150 (17.1)

Positive (4? nodes) 59 (9.8) 33 (3.8)

ER positivity 461 (76.8) 677 (77.4) P = 0.86

PR positivity 451 (75.2) 659 (75.3) P = 1.00

HER2 status (n = 786)

0 38 (12.5) 98 (20.3) P = 0.004

1 86 (28.3) 147 (30.5)

2 136 (44.7) 176 (36.5)

3 44 (14.5) 61 (12.7)

Age; mean(SD) 56.9 (4.7) 56.8 (4.6) P = 0.83

Ki67; mean (SD)

(n = 1041) 34.7 (16.0) 21.3 (10.4) P \ 0.001

Ki67 C 20; n (%) 305 (74.6) 341 (54.0) P \ 0.001

Ki67 C 25; n (%) 279 (68.2) 221 (35.0) P \ 0.001

Ki67 C 30; n (%) 246 (60.1) 127 (20.1) P \ 0.001

Chemo (n = 1418) 178 (30.0) 107 (13.0) P \ 0.001

NPI

Excellent 115 (19.2) 187 (21.4) P \ 0.001

Good 166 (27.7) 309 (35.3)

Moderate I 160 (26.7) 242 (27.7)

Moderate II 87 (14.5) 85 (9.7)

Poor 72 (12.0) 52 (5.9)

10-year distant recurrence

%; (95% CI)

19.9 7.9 P \ 0.001

(16.3, 23.5) (5.9, 9.9)

10-year breast cancer

mortality %; (95% CI)

22.4 7.9 P \ 0.001

(18.8, 26.0) (5.9, 9.9)

Comparison of prognostic features, distant recurrence and mortality

between SDBCs and symptomatic cancers. The figures are rounded to

one decimal place. Mortality and distant recurrence figures are

derived from Kaplan–Meier curves and were lower in SDBC com-

pared to symptomatic cancers at 10 years

Breast Cancer Res Treat (2013) 138:359–368 361

123

Mortality data for the operable SDBCs diagnosed in

2001/2002 that were submitted to the NHSBSP/ABS Audit

was utilized to validate our findings. The NHSBSP/ABS

Audit prospectively records data on tumour grade, size and

node status for SDBCs diagnosed in the U.K. Mortality

data are obtained by flagging the patients at cancer regis-

tries and are complete for all patients for a minimum of

5 years follow-up. Chemotherapy use was obtained from

the same dataset in the adjuvant therapy section of the

Audit.

Statistical analysis

Data were analysed using the statistical software package

SPSS version 15.0. The simple chi-square test and the two-

sample t-test were employed to compare the distribution of

pathological features between women with screen-detected

and symptomatic cancers. The assessment of factors

affecting recurrence and survival was made using Kaplan–

Meier plots and the log-rank test. The factors, tumour size

and number of nodes, involved were initially assessed as

continuous variables, to compare recurrence and mortality

between SDBC and symptomatic cancers. Mortality rates

are estimated from the survival proportion estimates at

each uncensored survival time life tables, derived from the

Kaplan–Meier analysis. Smoothed annual mortality rates

were calculated by ER and diagnosis group as described

previously [20]. Subsequently, Cox proportional hazards

regression models were employed to evaluate the inde-

pendent predictive power of diagnostic mode (symptomatic

or SDBC) after adjusting for statistically significant

tumour/patient characteristics (identified from size, grade,

node status, ER and PR status, Ki67, chemotherapy).

Results

After adjusting for tumour grade, size, node and ER status,

diagnosis by screening was associated with an independent

reduced risk of distant recurrence RR = 0.43; (95% CI

0.31–0.57) and breast cancer mortality RR = 0.42

(0.31–0.57) (Table 2). The smoothed annual mortality rates

showed the expected peak for cancer deaths in the 5 years

after surgery for symptomatic cancers (ER negative 5.6%/

year: ER positive 8.7%/year), whereas there was no peak

(increase in mortality or recurrence) in the first 5 years (or

subsequently) in ER positive SDBC (1.8%/year)

(P B 0.001: Fig. 2). Breast Cancer Survival for the study

population was 94% at 5 years. In 875 women with

SDBCs, overall 5 year cancer survival was 96.4%, com-

pared with 87.9% in 600 women with symptomatic cancers

(P \ 0.001).

Fig. 1 CONSORT diagram


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Node positivity was higher in symptomatic cancers

(35%) compared with SDBC (21%: P \ 0.001: Table 1).

The SDBCs were smaller (P \ 0.001), but no difference in

grade, ER or PR status was found (Table 1). Adjuvant

chemotherapy was given to 13% of SDBC and 30% of

symptomatic cancers. Distant recurrence was higher in

symptomatic (19.9% at 10 years) compared with SDBC

(7.9%) (P \ 0.001). Amongst SDBCs, regardless of grade

or ER status, only 13 out of 536 (Kaplan–Meier adjusted

percentage 2.5%) women with small tumours (\15 mm)

Table 2 Univariate and

multivariate analysis of breast

cancer survival

Univariate and multivariate

analysis of breast cancer

survival indicating mode of

detection, size, grade, ER

positivity and node status

independently predicted

survival. Ki67 and HER2 were

not available in the early years,

and the number of values is less

Variables (n = 1475) Univariate analysis Multivariate analysis

Hazard ratio (95% CI) P-value Hazard ratio (95% CI) P-value

Mode of detection

Symptomatic 1 1

Screen detected 0.31 (0.23–0.42) \0.001 0.42 (0.31, 0.57) \0.001

Size

\15 mm 1 1

15–25 mm 4.22 (2.85–6.24) \0.001 2.15 (1.43–3.25) \0.001

[25 mm 12.2 (8.05–18.5) \0.001 4.11 (2.62–6.46) \0.001

Grade

I 1 1

II 3.99 (2.16–7.36) \0.001 2.98 (1.61–5.54) 0.001

III 10.2 (5.62–18.5) \0.001 5.90 (3.20–10.8) \0.001

Node status

Negative 1 1

Positive (1–3 nodes) 4.19 (3.01–5.84) \0.001 2.43 (1.71–3.44) \0.001

Positive (4? nodes) 14.0 (9.83–20.1) \0.001 4.87 (3.29–7.20) \0.001

ER status

Negative 1 1

Positive 0.58 (0.43–0.78) \0.001 0.68 (0.50–0.92) 0.012

PR status

Negative 1

Positive 0.60 (0.44–0.81) 0.001

HER2 status (n = 786)

0 1

1 0.81 (0.44–1.49) 0.49

2 0.94 (0.53–1.65) 0.82

3 2.42 (1.33–4.42) 0.004

Age

Each 10 year increase 0.90 (0.66–1.22) 0.49

Ki67 (n = 1041)

Each 10 unit increase 1.47 (1.33–1.63) \0.001

Ki67 \ 20 1

Ki67 C 20 3.63 (2.30–5.72) \0.001

Chemotherapy (n = 1418)

No 1

Yes 6.47 (4.85–8.63) \0.001

NPI

Excellent 1

Good 5.17 (1.55–17.2) 0.007

Moderate I 14.1 (4.41–45.3) \0.001

Moderate II 36.2 (11.3–116) \0.001

Poor 89.3 (28.1–284) \0.001


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had evidence of distant recurrence by 60 months compared

with 20/217 (9.7%) symptomatic cancers (Table 2).

Epithelial proliferation

The Ki67 scores were lower in SDBC (see Table 3:

P = 0.001). Even in grade III cancers, SDBC ER positive

tumours (n = 137) had a mean Ki67 of 27.4% (range

5.8–53.1%) compared with 46.3% (range 12.3–78.9%) in

symptomatic cancers (P \ 0.001). In both symptomatic

and SDBC, higher epithelial proliferation (Ki67 score) was

associated with earlier distant recurrence (P = 0.001 and

P = 0.041, respectively) and breast cancer mortality at

5 years (P = 0.005 and P \ 0.001, respectively).

For SDBCs, there was a reduced risk of mortality for ER

positive cancers compared with ER negative tumours

(P = 0.003; log-rank test).

Table 3 NPI index score and mortality in SDBC and symptomatic cancers—ER positive patients only

Index score Screened cohort

N (%) Ki67%

mean (SD)

Grade III

(%)

Node

positive

(%)

Chemo

(%)

10-year distant

recurrence

% (CI)

10-year breast

cancer mortality

% (CI)

5-year overall

mortality

EPG 156 10.7 0 0 0 4.8 0 1.3

(23.0) (4.7) (1.2–8.4)

GPG 256 20.5 0 12 1 5.7 2.6 1.2

(37.3) (8.7) (2.7–8.7) (0.2–5.0)

MPG1 175 24.8 64 23 9 7.4 6.4 2.4

(25.8) (9.7) (3.2–11.6) (2.0–10.8)

MPG2 60 27.5 77 58 38 8.7 21.2 6.7

(8.0) (9.0) (1.3–16.1) (9.0–33.4)

PPG 30 27.5 93 100 89 46.9 49.2 13.3

(4.4) (6.2) (22.9–70.9) (26.6–71.8)

Total 677 20.6 28 20 10 7.5 6.8 2.6

(9.9) (5.3–9.7) (4.6–9.0)

Index score Symptomatic cohort

N (%) Ki67%

mean (SD)

Grade III

(%)

Node

positive

(%)

Chemo

(%)

10-year distant

recurrence

% (CI)

10-year breast

cancer mortality

% (CI)

5-year

overall

mortality

EPG 94 14.9 0 0 0 7.8 1.1 1.1

(20.4) (5.0) (2.2–13.4) (0–3.3)

GPG 132 31.4 0 8 8 14.7 9.3 3.8

(28.6) (12.5) (8.2–21.1) (3.5–15.1)

MPG1 116 40.8 41 36 26 19.4 17.6 8.0

(25.2) (14.9) (11.6–27.2) (10.0–25.2)

MPG2 64 40.8 52 89 82 30 39.8 22.4

(13.9) (13.4) (16.6–43.4) (26.6–53.0)

PPG 55 36.4 76 100 76 59.5 66.4 31.5

(11.9) (15.3) (42.9–76.1) (52.8–80.0)

Total 461 33.7 27 36 29 20.7 20.4 10.1

(15.6) (16.7–24.7) (16.4–24.4)

Log-rank test (distant recurrence): EPG P = 0.33, GPG P = 0.001, MPG1 P = 0.005, MPG2 P = 0.009, PPG P = 0.28

Log-rank test (breast cancer mortality): EPG P = 0.20, GPG P = 0.001, MPG1 P = 0.001, MPG2 P = 0.034, PPG P = 0.015

NPI Index Score and mortality in SDBC and symptomatic cancers in ER positive cancers only. Ki67 was lower for SDBC compared with

symptomatic cancers in every NPI group. Differences in survival for NPI groups for distant recurrence and mortality were seen for SDBC

compared with symptomatic cancers for all scores except in the EPG


123

Comparison of Nottingham prognostic index groups

The SDBC had a better prognosis despite less chemother-

apy use (Table 3) in every NPI group (except the Excellent

Prognostic Group [EPG]) compared with symptomatic

cancers. Cancer survival in SDBC was the equivalent of

one NPI group better than symptomatic cancers (Fig. 3). In

the MPG1, 26% of ER positive symptomatic cancers had

chemotherapy but mortality at 5 years was 8%, whereas

mortality of 2% at 5 years occurred in MPG-1 SDBC

despite only 9% receiving chemotherapy (P = 0.001).

Calculating the NPI for the 6737 operable SDBCs

diagnosed and submitted to the ABS Audit in 2001–2002,

similar 5 year relative survival and breast cancer mortality

were found for equivalent NPI scores to those found for

SDBCs diagnosed in Manchester (Table 3). Chemotherapy

use in the SDBC in NPI groups submitted to the ABS Audit

(Table 4), revealed minimal use in both EPG and Good

Prognostic Group (GPG) cancers. Even in the MPG1

group, chemotherapy use was low, considering 40% were

grade III, 33% node positive and 25% ER negative but

given the 4% breast cancer-specific mortality at 5 years,

the effect of chemotherapy on mortality will have been less

than 1%.

Improvements in survival have occurred for U.K SDBC

since 1990 due to the increased use of adjuvant endocrine

therapy. Relative survival at 5 years is now 97.2% in

SDBC compared to 77.6% in symptomatic cancers, but this

improved survival has mainly been achieved by combined

chemoendocrine therapy of the MPG2 and PPG cancers

(19% of SDBC population: Table 4).

Discussion

Breast cancer survival has improved dramatically in the

UK but remains poorer than many European countries

because of delayed diagnosis and late stage at diagnosis [9,

22]. Chemotherapy is advised by oncologists using the St

Gallen guidelines or NPI [10, 11, 14] on the basis of

pathological size, grade and node status [10, 11, 14]. If

chemotherapy is used according to guidelines derived from

symptomatic cancer trials, up to 40% of women with

SDBC would be candidates for chemotherapy [10, 11, 14].

Molecular profiling of cancers identifies ER positive

patients who do not benefit from the addition of chemo-

therapy to endocrine therapy [23]. Cancers detected by

breast screening had a reduced likelihood of death from

breast cancer at 10 years (RR 0.57) in three Scandinavian

and a Dutch study [1, 3, 6, 24]. A Norwegian study claimed

that most of the reduction in mortality was from adjuvant

therapy, not screening, based on short follow-up (average

2 years) and has been criticised, as most early deaths from

breast cancer occur in ER negative cancers patients in

whom adjuvant chemotherapy is mandatory (see Fig. 2).

The benefit of SDBC detection is unlikely to be seen with

such a short follow-up and will be significantly underesti-

mated in the context of this study [25]. The Dutch study

[23] found that despite 91% of their SDBC having no

adjuvant or hormone therapy alone, diagnosis by screening

independently predicted survival.

Cancer detection by screening was an independent

predictor of survival on multivariate analysis. In view of

claims of over-diagnosis of breast cancer by screening, it is

imperative that resources are not used to over-treat cancers

detected. Despite less adjuvant chemotherapy being given,

similar aged SDBC had a lower mortality compared with

symptomatic cancer patients in all prognostic factor sub-

groups, underlining that ER positive SDBC do not benefit

significantly from chemotherapy, confirming findings from

Holland [23].

The overall mortality (survival) of Manchester SDBCs

is similar to the National SDBC survival figures [17] and

the Scandinavian and Dutch studies [3, 6, 23]. National

SDBC survival figures from 2001 to 2002 show a 96.5%

overall survival at 10 years [17]. To avert arguments about

lead time bias, we matched groups for size, grade ER and

Fig. 2 Smoothed annual rate of mortality in ER positive and negative

SDBC and symptomatic breast cancers ER positive, SDBC had a low

5 year annual mortality, ranging between 0.1% and 1.8% at

60 months which was significantly lower than symptomatic ER

positive (blue line). ER negative breast cancers that were symptom-

atic had a significantly higher annual mortality rate than SDBC that

were ER negative. The overall difference between SDBC which were

ER positive and the other groups is significant (P = 0.001).

Chemotherapy use was 13% in the SDBC and 30% in the

symptomatic population


123

node status using the NPI but the observed survival dif-

ferences remained (Table 3). The excellent survival in size

B15 mm ER positive, node negative breast cancer occur-

red in the absence of chemotherapy. The excellent survival

of SDBC in the Excellent Prognostic Group (EPG), GPG

and MPG1 needs to be recognised when deciding adjuvant

therapy. No convergence in survival was evident after

10 years, indicating the difference is unlikely to be due to

lead time bias; a similar finding to others [1, 6, 7]. More-

over, the EBCTCG metaanalysis for the 50–70 year old

age groups shows a 3–5% absolute reduction in breast

cancer mortality in the first 5 years after chemotherapy but

no increased benefit at 15 years; thus even if there is a lead

time bias of 5 years in SDBC, there is no published evi-

dence chemotherapy will affect survival beyond the lead

time. The NHSBSP did not involve oncologists at its

inception because it was only deemed to operate until

cancer diagnosis. Oncologists need to appreciate the better

survival of SDBCs to avoid over-treatment. Effectively,

SDBC MPG1 survival is equivalent to symptomatic GPG

cancers.

Since this data is from several cohort studies, not ran-

domized trials, its interpretation needs some circumspec-

tion, but given the high cure rate in ER positive,

mammographically detected cancers, clinical trials assess-

ing the role of chemotherapy in this setting are unlikely as

they would require a large sample size, at huge economic

cost and would have a high likelihood of returning a neg-

ative result where the endpoint was mortality or recurrence.

Chemotherapy works within 5 years of administration

by killing proliferating cells, reducing the early peak of

mortality seen in symptomatic cancers (Fig. 2). Although

grade takes account of tumour mitotic rate, within grades,

widely different epithelial proliferation rates were seen.

The proliferation rate (Ki67) was a predictor of survival

and was lower in SDBC (i.e. they are slower growing) than

symptomatic cancers. The ER positive SDBC had no early

peak in mortality and a lower annual hazard ratio of death

compared with the ER negative SDBC or symptomatic

cancers. The lower epithelial proliferation in SDBC pro-

vides a biological rationale for their lower mortality, and a

reason why chemotherapy would be less effective [18]. The

21-gene Recurrence Test for ER positive, HER2 negative

breast cancer identifies patients who do not benefit from

chemotherapy on the basis of a high ER/PR score and a low

proliferation score [11].

Most SDBCs, had a Ki67 of\20%, were slow growing

and thus unlikely to benefit from chemotherapy. Since the

reduction in mortality benefit of chemotherapy occurs

within 5 years of treatment, administering chemotherapy to

ER positive SDBC will have no effect on mortality as there

is no early mortality or recurrence peak (Fig. 2).

The addition of chemotherapy to Tamoxifen, in ER

positive, node positive postmenopausal breast cancers led

to reduced mortality, but the benefits were largely confined

to heavily node positive and women\65 years of age [12].

This confirms no benefit will occur in small, node negative,

or less than 4 node positive, ER positive SDBC. Clinical

signs such as a lump are associated with invasiveness,

faster growth and increased mortality [3, 6]. Almost 50%

of SDBC are impalpable, requiring excision by a locali-

zation technique and have a better survival [1–3, 6].

In Manchester, chemotherapy was given to the Poor

Prognostic Groups, until the EBCTCG report in 1998

supporting its wider use in symptomatic cancers [10].

Overall, SDBCs had a survival of 90.7% at 10 years and

Table 4 NHSBSP and ABS at BASO breast screening audit data for invasive SDBCs diagnosed in 2001/2002

NPI 1990–1991 1996–1997 N 2001–2002 Grade

III (%)

Node

positive

(%)

Chemo

(%)

5 year relative

survival

2001–2002

5 year breast cancer

cause specific

mortality (%)

EPG 102.1 100.5 1774 0 0 1 102.2% 0

\2.4 (100.7, 103.6) (99.3–101.7) (101.5, 102.9)

GPG 98.2 98.6 2397 0 10 5 100.1% 1

2.41–3.4 (96.4, 100.1) (97.3–99.9) (99.2, 100.9)

MPG1 93.3 94.2 1470 40 33 32 96.7% 4

[3.4–4.4 (90.5, 96.1) (92.2–96.3) (95.2, 98.1)

MPG2 79.9 87.4 696 52 74 56 92.0% 9

4.41–5.4 (74.8, 85.1) (84.0–90.8) (89.4, 75.3)

PPG 55.8 71.5 400 69 100 64 70.4% 28

[5.4 (47.9, 63.6) (65.5–77.5) (65.4, 75.3)

ABS at BASO Audit data for SDBC diagnosed in 2001/02, NPI scores predicted overall mortality at 5 years. Recurrence and mortality rate

estimates derived from Kaplan–Meier curves. Chemotherapy use in tumours with similar scores 2001/2002 indicates under treatment in MPG2

and PPG nationally. Note improvements in survival in SDBC nationally have mainly come from improved treatment of MPG2 and PPG cancers

by chemo and endocrine therapy


123

96.4% at 5 years (a figure similar to the 96.5% 5 year

survival of SDBCs in the ABS Audit).

For all groups, where the mortality from breast cancer is

less than 10%, absolute reduction in mortality (1%) pro-

duced by chemotherapy will be outweighed by chemo-

therapy induced morbidity (1–4%) [12, 13]. The lack of

survival benefit has been demonstrated in small, ER posi-

tive SDBCs regardless of grade or node status as 10-year

survival was 99% in the absence of chemotherapy.

Selection criteria for type of adjuvant therapy

The programme Adjuvant! Online is used in the U.S. [11]

and recommended by NICE in the U.K., for making deci-

sions about the kind of adjuvant therapy to prescribe. Using

this programme, a grade III, 15 mm node negative or a

grade II node positive breast cancer would have a survival

of 76.6–80.4% at 10 years, which in an ER positive patient

is improved by approximately 4% using adjuvant endo-

crine therapy. This is in keeping with the survival of the

symptomatic ER positive patients in Manchester. In ER

positive SDBCs (10% received chemotherapy), there was a

breast cancer mortality of 1.7% at 5 years and 6.8% at

10 years, which is three-fold less than that suggested by

Adjuvant! Online. The 5 year data for survival for MPG1

in the ABS Audit shows a mortality of 4%, which is three-

fold lower than expected but consistent with Scandinavian

SDBC survival. Similar data were found in Holland, where

Adjuvant! Online underestimated SDBC survival by 3–5%

[23] in the absence of chemotherapy.

The survival of SDBC, for identical ‘anatomical factors’

(grade, size and node status), is better than symptomatic

cancers, and we must avoid over-treating these cancers. For

ER positive, HER2 negative breast cancer, adjuvant

endocrine therapy is all that is required for those in NPI

EPG, GPG and MPG1. Since this constitutes 70% of

SDBC, the result of treating these patients who are ER

positive and HER2 negative with chemotherapy, in terms

of significant morbidity, has to be weighed with the eco-

nomic costs and the lack of benefit of the treatment.

Consensus guidelines about the management of SDBC

need to be drawn up internationally.

Molecular profiling of breast cancers has been pro-

posed as a method to identify tumours at the risk of early

recurrence to select for chemotherapy [25]. Oncotype DX

uses ER, PR, HER2 and Ki67 to identify a low-risk group

with a recurrence of 14% at 10 years who do not benefit

from chemotherapy, but ER positive SDBC in GPG/

MPG1 have a 7% mortality at 10 years, so its expense

(around £2500 per patient) would not be justified where it

will not add further information in a population at low

risk of mortality.

The SDBC overexpressing HER2 had a higher mortality

(RR 2.84) but the effect of HER2 expression on mortality

was non-significant after adjusting for node status, grade

and tumour size. The SDBCs have a better survival than

symptomatic cancers for all grades, node and ER status.

The individualisation of therapy for breast cancer is now

possible on the basis of mode of detection, ER status and

NPI score at little extra cost.

The need for chemotherapy and hormonal therapy in

SDBC can be targeted with consequent improvement in

quality of life and reduced costs to the NHS.

Acknowledgments The authors appreciate and acknowledge the

contribution of the Association of Breast Surgeons at the British

Association of Surgical Oncology membership for contributing

patients to the ABS at BASO Audit and the contribution of the

members of the NHS Cancer Screening Programmes for the data. The

Follow-up numbers Symptomatic Months 0 12 24 36 48 60 72 84 96 108 120 GPG 132 132 132 131 130 121 108 98 77 58 29 MPG1 116 116 115 115 110 100 88 81 66 53 30 MPG2 64 64 64 60 56 48 37 34 27 17 12 PGP 55 54 53 46 44 38 17 14 12 8 6

SDBCMonths 0 12 24 36 48 60 72 84 96 108 120 GPG 256 156 156 255 253 236 224 218 184 155 115 MPG1 175 175 174 172 170 158 150 136 116 92 60 MPG2 60 60 59 59 57 54 48 44 35 22 13 PGP 30 30 30 29 29 28 19 19 16 12 6

Fig. 3 Breast cancer mortality (ER positives) follow-up numbers.

Proportion of breast cancer survival and NPI scores for ER positive

SDBC and symptomatic cancers plotted by NPI score for SDBC and

symptomatic breast cancers. *Log rank test. (P \ 0.001) Calculation

of NPI between groups revealed, in every group (except the EPG),

that SDBC had a better prognosis despite less chemotherapy use.

Kaplan–Meier curve showing breast cancer survival plotted by NPI.

*Log rank test. (P \ 0.001). Note SDBC have a survival approxi-

mately one NPI group better than symptomatic cancer


123

authors thank the South Manchester Multi-Disciplinary Team mem-

bers who provided surgical treatment for these patients and the

radiologists who provided diagnosis and detection of the breast

cancers.

Funding Funding was not obtained to carry out this study.

Conflict of interest The authors declare they have no competing

interests.

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